Inpatient hypoglycaemia; should we should we focus on the guidelines, the targets or our tools?

In their thought‐provoking commentary, Levy et al. [1] explore the possible unintended consequences of United Kingdom (UK) guideline targets on the high frequency of hypoglycaemia in people with diabetes who are hospitalized. The authors cite the National Institute for Health and Care Excellence (NICE) and the Joint British Diabetes Societies (JBDS) guidelines pertaining to inpatient, surgical and pregnancy diabetes care. These guidelines suggest using lower limits of glucose targets varying from 4.0 to 6.0 mmol/l [2–4]. Levy et al. propose a lower glucose limit of 5 mmol/l with the catchphrase ‘stop at 5 and keep the inpatient alive’

Hypocapnia Alone Fails to Provoke Important Electrocardiogram Changes in Coronary Artery Diseased Patients

Background: There is still an urgent clinical need to develop non-invasive diagnostic tests for early ischemic heart disease because, once angina occurs, it is too late. Hypocapnia has long been known to cause coronary artery vasoconstriction. Some new cardiology tests are accompanied by the claim that they must have potential diagnostic value if hypocapnia enhances their cardiac effects in healthy subjects. But no previous study has tested whether hypocapnia produces bigger cardiac effects in patients with angina than in healthy subjects. Methods: Severe hypocapnia (a PetCO2 level of 20 mmHg) lasting >15 min was mechanically induced by facemask, while conscious and unmedicated, in 18 healthy subjects and in 10 patients with angina and angiographically confirmed coronary artery disease, awaiting by-pass surgery. Each participant was their own control in normocapnia (where CO2 was added to the inspirate) and the order of normocapnia and hypocapnia was randomized. Twelve lead electrocardiograms (ECG) were recorded and automated measurements were made on all ECG waveforms averaged over >120 beats. 2D echocardiography was also performed on healthy subjects. Results: In the 18 healthy subjects, we confirm that severe hypocapnia (a mean PetCO2 of 20 ± 0 mmHg, P 0.05) on their electro- or echocardiogram. All 10 angina patients tolerated the mechanical hyperventilation well, with minimal discomfort. Hypocpania caused a similar increase in V1 (by 39%, P 0.05 vs. healthy controls) and did not induce angina. Its effects were no greater in patients who did not take β-blockers, or did not take organic nitrates, or had the worst Canadian Cardiovascular Society scores. Conclusion: Non-invasive mechanical hyperventilation while awake and unmedicated is safe and acceptable, even to patients with angina. Using it to produce severe and prolonged hypocapnia alone does produce significant ECG changes in angina patients. But its potential diagnostic value for identifying patients with coronary stenosis requires further evaluation

Ultrastructural studies in APP/PS1 mice expressing human ApoE isoforms: implications for Alzheimer’s disease

Alzheimer’s disease is characterized in part by extracellular aggregation of the amyloid-β peptide in the form of diffuse and fibrillar plaques in the brain. Electron microscopy (EM) has made an important contribution in understanding of the structure of amyloid plaques in humans. Classical EM studies have revealed the architecture of the fibrillar core, characterized the progression of neuritic changes, and have identified the neurofibrillary tangles formed by paired helical filaments (PHF) in degenerating neurons. Clinical data has strongly correlated cognitive impairment in AD with the substantial synapse loss observed in these early ultrastructural studies. Animal models of AD-type brain amyloidosis have provided excellent opportunities to study amyloid and neuritic pathology in detail and establish the role of neurons and glia in plaque formation. Transgenic mice overexpressing mutant amyloid precursor protein (APP) alone with or without mutant presenilin 1 (PS1), have shown that brain amyloid plaque development and structure grossly recapitulate classical findings in humans. Transgenic APP/PS1 mice expressing human apolioprotein E isoforms also develop amyloid plaque deposition. However no ultrastructural data has been reported for these animals. Here we show results from detailed EM analysis of amyloid plaques in APP/PS1 mice expressing human isoforms of ApoE and compare these findings with EM data in other transgenic models and in human AD. Our results show that similar to other transgenic animals, APP/PS1 mice expressing human ApoE isoforms share all major cellular and subcellular degenerative features and highlight the identity of the cellular elements involved in Aβ deposition and neuronal degeneration

Employment status at time of first hospitalization for heart failure is associated with death and rehospitalization for heart failure

Background: Employment status at time of first heart failure (HF) hospitalization may be an indicator of both self-perceived and objective health status. In this study, we examined the association between employment status and the risk of all-cause mortality and recurrent HF hospitalization in a nationwide cohort of patients with HF. Methods and Results: We identified all patients of working age (18-60 years) with a first HF hospitalisation in the period 1997-2015 in Denmark, categorized according to whether or not they were part of the workforce at time of the index admission. The primary outcome was death from any cause and the secondary outcome was readmission for HF. Cumulative incidence curves, binomial regression and Cox regression models were used to assess outcomes. Of 25571 patients with a first hospitalization for HF, 15428 (60%) were part of the workforce at baseline. Patients in the workforce were significantly younger (53 vs. 55 years) more likely to be male (75% vs 64%) and less likely to have diabetes (13% vs 22%) and chronic obstructive pulmonary disease (5% vs 10%), all p-values <0.001. Not being part of the workforce was associated with a significantly higher risk of death (HR: 1.59 [95% CI 1.50–1.68]) and rehospitalisation for HF (HR: 1.09 [95% CI 1.05–1.14]), in analyses adjusted for age, sex, comorbidities, education level, calendar time, duration of first HF hospitalization. Conclusion: Not being part of the workforce at time of first HF hospitalization was independently associated with increased mortality and recurrent HF hospitalization

A randomized trial to determine the impact on compliance of a psychophysical peripheral cue based on the Elaboration Likelihood Model

Objective: Non-compliance in clinical studies is a significant issue, but causes remain unclear. Utilizing the Elaboration Likelihood Model of persuasion, this study assessed the psychophysical peripheral cue ‘Interactive Voice Response System (IVRS) call frequency’ on compliance. Methods: 71 participants were randomized to once daily (OD), twice daily (BID) or three times daily (TID) call schedules over two weeks. Participants completed 30-item cognitive function tests at each call. Compliance was defined as proportion of expected calls within a narrow window (± 30 min around scheduled time), and within a relaxed window (− 30 min to + 4 h). Data were analyzed by ANOVA and pairwise comparisons adjusted by the Bonferroni correction. Results: There was a relationship between call frequency and compliance. Bonferroni adjusted pairwise comparisons showed significantly higher compliance (p = 0.03) for the BID (51.0%) than TID (30.3%) for the narrow window; for the extended window, compliance was higher (p = 0.04) with OD (59.5%), than TID (38.4%). Conclusion: The IVRS psychophysical peripheral cue call frequency supported the ELM as a route to persuasion. The results also support OD strategy for optimal compliance. Models suggest specific indicators to enhance compliance with medication dosing and electronic patient diaries to improve health outcomes and data integrity respectively

Biomarkers and low risk in heart failure. Data from COACH and TRIUMPH

Aim Traditionally, risk stratification in heart failure (HF) emphasizes assessment of high risk. We aimed to determine if biomarkers could identify patients with HF at low risk for death or HF rehospitalization. Methods and results This analysis was a substudy of The Coordinating Study Evaluating Outcomes of Advising and Counselling in Heart Failure (COACH) trial. Enrolment of HF patients occurred before discharge. We defined low risk as the absence of death and/or HF rehospitalizations at 180 days. We tested a diverse group of 29 biomarkers on top of a clinical risk model, with and without N-terminal pro-B-type natriuretic peptide (NT-proBNP), and defined the low risk biomarker cut-off at the 10th percentile associated with high positive predictive value. The best performing biomarkers together with NT-proBNP and cardiac troponin I (cTnI) were re-evaluated in a validation cohort of 285 HF patients. Of 592 eligible COACH patients, the mean (± SD) age was 71 (± 11) years and median (IQR) NT-proBNP was 2521 (1301-5634) pg/mL. Logistic regression analysis showed that only galectin-3, fully adjusted, was significantly associated with the absence of events at 180 days (OR 8.1, 95% confidence interval 1.06-50.0, P = 0.039). Galectin-3, showed incremental value when added to the clinical risk model without NT-proBNP (increase in area under the curve from 0.712 to 0.745, P = 0.04). However, no biomarker showed significant improvement by net reclassification improvement on top of the clinical risk model, with or without NT-proBNP. We confirmed our results regarding galectin-3, NT-proBNP, and cTnI in the independent validation cohort. Conclusion We describe the value of various biomarkers to define low risk, and demonstrate that galectin-3 identifies HF patients at (very) low risk for 30-day and 180-day mortality and HF rehospitalizations after an episode of acute HF. Such patients might be safely discharged

A modular analogue of Morozov's theorem on maximal subalgebras of simple Lie algebras

Let $G$ be a simple algebraic group over an algebraically closed field of characteristic $p>0$ and suppose that $p$ is a very good prime for $G$. We prove that any maximal Lie subalgebra $M$ of $\mathfrak{g} = {\rm Lie}(G)$ with ${\rm rad}(M) \ne 0$ has the form $M = {\rm Lie}(P)$ for some maximal parabolic subgroup $P$ of $G$. We show that the assumption on $p$ is necessary by providing a counterexample for groups type ${\rm E}_8$ over fields of characteristic $5$. Our arguments rely on the main results and methods of the classification theory of finite dimensional simple Lie algebras over fields prime characteristic.Comment: 42 pages; this version of the preprint is accepted for publication in "Advances in Mathematics

Why asthma still kills: The national review of asthma deaths (NRAD)

Advancements in drug treatments, applied research and the development of evidence-based clinical guidelines have contributed to the reduction of deaths from asthma over the past 50 years.Previous confidential enquiries have suggested that avoidable factors play a part in as many as threequarters of cases of asthma death. These studies have often been small, conducted locally and undertaken at a considerable time after death. The National Review of Asthma Deaths (NRAD), reported here, is the first national investigation of asthma deaths in the UK and the largest study worldwide to date. Work on the NRAD was undertaken over a 3-year period and was one element of the Department of Health inEngland’s Respiratory Programme. The primary aim of the NRAD was to understand the circumstances surrounding asthma deaths in the UK in order to identify avoidable factors and make recommendations to improve care and reduce the number of deaths.Asthma deaths occurring between February 2012 and January 2013 were identified through the Office for National Statistics (ONS) for England and Wales, the Northern Ireland Statistics and Research Agency(NISRA) and the National Records of Scotland (NRS). Extensive information about each death was sought from multiple sources, including primary, secondary and tertiary care, as well as ambulance, paramedic and out-of-hours care providers. 374 local coordinators were appointed in 297 hospitals across the NHS to collect and submit information to the project team, and 174 expert clinical assessors were recruited from primary, secondary and tertiary care throughout the UK to join expert panels that reviewed data. Each assessor participated in one or more expert panels, during which all information gathered on each death, including post-mortem reports, was reviewed by two assessors in detail, and this was followed by discussion and a consensus agreement of avoidable factors and recommendations by the whole panel.Data were available for analysis on 195 people who were thought to have died from asthma during the review period and the key findings relate to this group. Denominators vary according to where data were missing